Kurowska-Stolarska M, Alivernini S. Synovial tissue macrophages: friend or foe? RMD Open. 2017;3:e000527.
Meyer A, Sienes RE, Nijim W, Zanotti B, Umar S, Volin MV, et al. Syntenin-1-mediated arthritogenicity is advanced by reprogramming RA metabolic macrophages and Th1 cells. Ann Rheum Dis. 2023;82:483–495.
Van Raemdonck K, Umar S, Palasiewicz K, Volin MV, Elshabrawy HA, Romay B, et al. Interleukin-34 reprograms glycolytic and osteoclastic rheumatoid arthritis macrophages via syndecan 1 and macrophage colony-stimulating factor receptor. Arthritis Rheumatol. 2021;73:2003–2014.
Lewis MJ, Barnes MR, Blighe K, Goldmann K, Rana S, Hackney JA, et al. Molecular portraits of early rheumatoid arthritis identify clinical and treatment response phenotypes. Cell Rep. 2019;28:2455–2470.e2455.
Orange DE, Yao V, Sawicka K, Fak J, Frank MO, Parveen S, et al. RNA identification of PRIME cells predicting rheumatoid arthritis flares. N Engl J Med. 2020;383:218–228.
Xu WD, Firestein GS, Taetle R, Kaushansky K, Zvaifler NJ. Cytokines in chronic inflammatory arthritis. II. Granulocyte-macrophage colony-stimulating factor in rheumatoid synovial effusions. J Clin Invest. 1989;83:876–882.
Fiehn C, Wermann M, Pezzutto A, Hufner M, Heilig B. Plasma GM-CSF concentrations in rheumatoid arthritis, systemic lupus erythematosus and spondyloarthropathy]. Z Rheumatol. 1992;51:121–126.
Noster R, Riedel R, Mashreghi MF, Radbruch H, Harms L, Haftmann C, et al. IL-17 and GM-CSF expression are antagonistically regulated by human T helper cells. Sci Transl Med. 2014;6:241ra280.
Sheng W, Yang F, Zhou Y, Yang H, Low PY, Kemeny DM, et al. STAT5 programs a distinct subset of GM-CSF-producing T helper cells that is essential for autoimmune neuroinflammation. Cell Res. 2014;24:1387–1402.
Darrieutort-Laffite C, Boutet MA, Chatelais M, Brion R, Blanchard F, Heymann D, et al. IL-1beta and TNFalpha promote monocyte viability through the induction of GM-CSF expression by rheumatoid arthritis synovial fibroblasts. Mediators Inflamm. 2014;2014:241840.
Fuentelsaz-Romero S, Cuervo A, Estrada-Capetillo L, Celis R, Garcia-Campos R, Ramirez J, et al. GM-CSF Expression and macrophage polarization in joints of undifferentiated arthritis patients evolving to rheumatoid arthritis or psoriatic arthritis. Front Immunol. 2020;11:613975.
Wada H, Noguchi Y, Marino MW, Dunn AR, Old LJ. T cell functions in granulocyte/macrophage colony-stimulating factor deficient mice. Proc Natl Acad Sci USA. 1997;94:12557–12561.
Sakamaki K, Miyajima I, Kitamura T, Miyajima A. Critical cytoplasmic domains of the common beta subunit of the human GM-CSF, IL-3 and IL-5 receptors for growth signal transduction and tyrosine phosphorylation. EMBO J. 1992;11:3541–3549.
Hamilton JA. GM-CSF in inflammation. J Exp Med. 2020;217:e20190945.
Lee KM, Jarnicki A, Achuthan A, Fleetwood AJ, Anderson GP, Ellson C, et al. CCL17 in inflammation and pain. J Immunol. 2020;205:213–222.
Achuthan A, Cook AD, Lee MC, Saleh R, Khiew HW, Chang MW, et al. Granulocyte macrophage colony-stimulating factor induces CCL17 production via IRF4 to mediate inflammation. J Clin Invest. 2016;126:3453–3466.
Campbell IK, Rich MJ, Bischof RJ, Dunn AR, Grail D, Hamilton JA. Protection from collagen-induced arthritis in granulocyte-macrophage colony-stimulating factor-deficient mice. J Immunol. 1998;161:3639–3644.
Yang YH, Hamilton JA. Dependence of interleukin-1-induced arthritis on granulocyte-macrophage colony-stimulating factor. Arthritis Rheum. 2001;44:111–119.
Cook AD, Braine EL, Campbell IK, Rich MJ, Hamilton JA. Blockade of collagen-induced arthritis post-onset by antibody to granulocyte-macrophage colony-stimulating factor (GM-CSF): requirement for GM-CSF in the effector phase of disease. Arthritis Res. 2001;3:293–298.
Dirksen U, Hattenhorst U, Schneider P, Schroten H, Gobel U, Bocking A, et al. Defective expression of granulocyte-macrophage colony-stimulating factor/interleukin-3/interleukin-5 receptor common beta chain in children with acute myeloid leukemia associated with respiratory failure. Blood. 1998;92:1097–1103.
Stanley E, Lieschke GJ, Grail D, Metcalf D, Hodgson G, Gall JA, et al. Granulocyte/macrophage colony-stimulating factor-deficient mice show no major perturbation of hematopoiesis but develop a characteristic pulmonary pathology. Proc Natl Acad Sci USA. 1994;91:5592–5596.
Taylor PC, Weinblatt ME, McInnes IB, Atsumi T, Strand V, Takeuchi T, et al. Anti-GM-CSF otilimab versus sarilumab or placebo in patients with rheumatoid arthritis and inadequate response to targeted therapies: a phase III randomised trial (contRAst 3). Ann Rheum Dis. 2023;82:1527–1537.
Lama M, Sarkar R, Ghosh B. Serum cytokine profiles in patients with rheumatoid arthritis before and after treatment with methotrexate. J Interferon Cytokine Res. 2023;43:344–350.
Umar S, Palasiewicz K, Volin MV, Romay B, Rahat R, Tetali C, et al. Metabolic regulation of RA macrophages is distinct from RA fibroblasts and blockade of glycolysis alleviates inflammatory phenotype in both cell types. Cell Mol Life Sci. 2021;78:7693–7707.
Pucino V, Certo M, Varricchi G, Marone G, Ursini F, Rossi FW, et al. Metabolic checkpoints in rheumatoid arthritis. Front Physiol. 2020;11:347.
Hollander AP, Corke KP, Freemont AJ, Lewis CE. Expression of hypoxia-inducible factor 1alpha by macrophages in the rheumatoid synovium: implications for targeting of therapeutic genes to the inflamed joint. Arthritis Rheum. 2001;44:1540–1544.
Tannahill GM, Curtis AM, Adamik J, Palsson-McDermott EM, McGettrick AF, Goel G, et al. Succinate is an inflammatory signal that induces IL-1beta through HIF-1alpha. Nature. 2013;496:238–242.
Mills EL, Kelly B, Logan A, Costa ASH, Varma M, Bryant CE, et al. Succinate dehydrogenase supports metabolic repurposing of mitochondria to drive inflammatory macrophages. Cell. 2016;167:457–470.e413.
Kraus F, Roy K, Pucadyil TJ, Ryan MT. Function and regulation of the divisome for mitochondrial fission. Nature. 2021;590:57–66.
Littlewood-Evans A, Sarret S, Apfel V, Loesle P, Dawson J, Zhang J, et al. GPR91 senses extracellular succinate released from inflammatory macrophages and exacerbates rheumatoid arthritis. J Exp Med. 2016;213:1655–1662.
Cramer T, Yamanishi Y, Clausen BE, Forster I, Pawlinski R, Mackman N, et al. HIF-1alpha is essential for myeloid cell-mediated inflammation. Cell. 2003;112:645–657.
Fearon U, Hanlon MM, Floudas A, Veale DJ. Cellular metabolic adaptations in rheumatoid arthritis and their therapeutic implications. Nat Rev Rheumatol. 2022;18:398–414.
Zhang F, Wei K, Slowikowski K, Fonseka CY, Rao DA, Kelly S, et al. Defining inflammatory cell states in rheumatoid arthritis joint synovial tissues by integrating single-cell transcriptomics and mass cytometry. Nat Immunol. 2019;20:928–942.
Zhang F, Jonsson AH, Nathan A, Millard N, Curtis M, Xiao Q, et al. Deconstruction of rheumatoid arthritis synovium defines inflammatory subtypes. Nature. 2023;623:616–624.
Alivernini S, MacDonald L, Elmesmari A, Finlay S, Tolusso B, Gigante MR, et al. Distinct synovial tissue macrophage subsets regulate inflammation and remission in rheumatoid arthritis. Nat Med. 2020;26:1295–1306.
Reynolds G, Gibbon JR, Pratt AG, Wood MJ, Coady D, Raftery G, et al. Synovial CD4 + T-cell-derived GM-CSF supports the differentiation of an inflammatory dendritic cell population in rheumatoid arthritis. Ann Rheum Dis. 2016;75:899–907.
Yamada H, Haraguchi A, Sakuraba K, Okazaki K, Fukushi JI, Mizu-Uchi H, et al. Th1 is the predominant helper T cell subset that produces GM-CSF in the joint of rheumatoid arthritis. RMD open. 2017;3:e000487.
Shiomi A, Usui T, Mimori T. GM-CSF as a therapeutic target in autoimmune diseases. Inflamm Regen. 2016;36:8.
Greven DE, Cohen ES, Gerlag DM, Campbell J, Woods J, Davis N, et al. Preclinical characterisation of the GM-CSF receptor as a therapeutic target in rheumatoid arthritis. Ann Rheum Dis. 2015;74:1924–1930.
Lee KMC, Achuthan AA. Hamilton JAGM-CSF: a promising target in inflammation and autoimmunity. Immunotargets Ther. 2020;9:225–240.
Bergstrom B, Sellden T, Bollmann M, Svensson MND, Ekwall AH. Methotrexate promotes the release of granulocyte-macrophage colony-stimulating factor from rheumatoid arthritis fibroblast-like synoviocytes via autocrine interleukin-1 signaling. Arthritis Res Ther. 2024;26:178.
Avci AB, Feist E, Burmester GR. Targeting GM-CSF in rheumatoid arthritis. Clin Exp Rheumatol. 2016;34:39–44.
Burmester GR, McInnes IB, Kremer J, Miranda P, Korkosz M, Vencovsky J, et al. A randomised phase IIb study of mavrilimumab, a novel GM-CSF receptor alpha monoclonal antibody, in the treatment of rheumatoid arthritis. Ann Rheum Dis. 2017;76:1020–1030.
Cook AD, Lee MC, Saleh R, Khiew HW, Christensen AD, Achuthan A, et al. TNF and granulocyte macrophage-colony stimulating factor interdependence mediates inflammation via CCL17. JCI Insight. 2018;3:e99249.
Papagoras C, Tsiami S, Chrysanthopoulou A, Mitroulis I, Baraliakos X. Serum granulocyte-macrophage colony-stimulating factor (GM-CSF) is increased in patients with active radiographic axial spondyloarthritis and persists despite anti-TNF treatment. Arthritis Res Ther. 2022;24:195.
Guo X, Wang S, Godwood A, Close D, Ryan PC, Roskos LK, et al. Pharmacodynamic biomarkers and differential effects of TNF- and GM-CSF-targeting biologics in rheumatoid arthritis. Int J Rheum Dis. 2019;22:646–653.
Fleischmann RM, van der Heijde D, Strand V, Atsumi T, McInnes IB, Takeuchi T, et al. Anti-GM-CSF otilimab versus tofacitinib or placebo in patients with active rheumatoid arthritis and an inadequate response to conventional or biologic DMARDs: two phase 3 randomised trials (contRAst 1 and contRAst 2). Ann Rheum Dis. 2023;82:1516–1526.
Wright HL, Cross AL, Edwards SW, Moots RJ. Effects of IL-6 and IL-6 blockade on neutrophil function in vitro and in vivo. Rheumatology (Oxford). 2014;53:1321–1331.
Lotfi N, Thome R, Rezaei N, Zhang GX, Rezaei A, Rostami A, et al. Roles of GM-CSF in the pathogenesis of autoimmune diseases: an update. Front Immunol. 2019;10:1265.
Poppensieker K, Otte DM, Schurmann B, Limmer A, Dresing P, Drews E, et al. CC chemokine receptor 4 is required for experimental autoimmune encephalomyelitis by regulating GM-CSF and IL-23 production in dendritic cells. Proc Natl Acad Sci USA. 2012;109:3897–3902.
Codarri L, Gyulveszi G, Tosevski V, Hesske L, Fontana A, Magnenat L, et al. RORgammat drives production of the cytokine GM-CSF in helper T cells, which is essential for the effector phase of autoimmune neuroinflammation. Nat Immunol. 2011;12:560–567.
Gu XY, Zhou LF, Zhang MS, Dai WJ, Chen SY, He SH, et al. Targeted NF-kappaB inhibition of asthmatic serum-mediated human monocyte-derived dendritic cell differentiation in a transendothelial trafficking model. Cell Immunol. 2009;260:14–20.
van de Laar L, van den Bosch A, van der Kooij SW, Janssen HL, Coffer PJ, van Kooten C, et al. A nonredundant role for canonical NF-kappaB in human myeloid dendritic cell development and function. J Immunol. 2010;185:7252–7261.
Nijjar JS, Abbott-Banner K, Alvarez Y, Aston N, Bass D, Bentley JH, et al. Efficacy, safety and tolerability of GSK3858279, an anti-CCL17 monoclonal antibody and analgesic, in healthy volunteers and patients with knee osteoarthritis pain: a phase I, randomised, double-blind, placebo-controlled, proof-of-mechanism and proof-of-concept study. Ann Rheum Dis. 2025;84:856–865.
Boyle Y, Hijma HJ, Rees J, Nijjar J, Panoilia E, Alvarez Y, et al. Randomized, placebo-controlled study on the effects of intravenous GSK3858279 (anti-CCL17) on a battery of evoked pain tests in healthy participants. Clin Transl Sci. 2024;17:e13873.
Hanlon MM, Smith CM, Canavan M, Neto NGB, Song Q, Lewis MJ, et al. Loss of synovial tissue macrophage homeostasis precedes rheumatoid arthritis clinical onset. Sci Adv. 2024;10:eadj1252.
Dowling JK, Afzal R, Gearing LJ, Cervantes-Silva MP, Annett S, Davis GM, et al. Mitochondrial arginase-2 is essential for IL-10 metabolic reprogramming of inflammatory macrophages. Nat Commun. 2021;12:1460.
Baseler WA, Davies LC, Quigley L, Ridnour LA, Weiss JM, Hussain SP, et al. Autocrine IL-10 functions as a rheostat for M1 macrophage glycolytic commitment by tuning nitric oxide production. Redox Biol. 2016;10:12–23.
Palmroth M, Kuuliala K, Peltomaa R, Virtanen A, Kuuliala A, Kurttila A, et al. Tofacitinib suppresses several JAK-STAT pathways in rheumatoid arthritis in vivo and baseline signaling profile associates with treatment response. Front Immunol. 2021;12:738481.
Valli A, Kuuliala K, Virtanen A, Kuuliala A, Palmroth M, Peltomaa R, et al. Tofacitinib treatment modulates the levels of several inflammation-related plasma proteins in rheumatoid arthritis and baseline levels of soluble biomarkers associate with the treatment response. Clin Exp Immunol. 2022;210:141–150.
Marzaioli V, Canavan M, Floudas A, Flynn K, Mullan R, Veale DJ, et al. CD209/CD14(+) dendritic cells characterization in rheumatoid and psoriatic arthritis patients: activation, synovial infiltration, and therapeutic targeting. Front Immunol. 2021;12:722349.
Canavan M, Marzaioli V, McGarry T, Bhargava V, Nagpal S, Veale DJ, et al. Rheumatoid arthritis synovial microenvironment induces metabolic and functional adaptations in dendritic cells. Clin Exp Immunol. 2020;202:226–238.
Palasiewicz K, Umar S, Romay B, Zomorrodi RK, Shahrara S. Tofacitinib therapy intercepts macrophage metabolic reprogramming instigated by SARS-CoV-2 Spike protein. Eur J Immunol. 2021;51:2330–2340.
Hanlon MM, McGarry T, Marzaioli V, Amaechi S, Song Q, Nagpal S, et al. Rheumatoid arthritis macrophages are primed for inflammation and display bioenergetic and functional alterations. Rheumatology. 2023;62:2611–2620.
Meyer A, Zack SR, Nijim W, Burgos A, Patel V, Zanotti B, et al. Metabolic reprogramming by Syntenin-1 directs RA FLS and endothelial cell-mediated inflammation and angiogenesis. Cell Mol Immunol. 2024;21:33–46.
van der Linden MP, Knevel R, Huizinga TW, van der Helm-van Mil AH. Classification of rheumatoid arthritis: comparison of the 1987 American College of Rheumatology criteria and the 2010 American College of Rheumatology/European League Against Rheumatism criteria. Arthritis Rheum. 2011;63:37–42.
Wang H, Sica RA, Kaur G, Galbo PM Jr., Jing Z, Nishimura CD, et al. TMIGD2 is an orchestrator and therapeutic target on human acute myeloid leukemia stem cells. Nat Commun. 2024;15:11.
Hou Y, Li Y, Xiang JF, Tilahun K, Jiang J, Corces VG, et al. TDP-43 chronic deficiency leads to dysregulation of transposable elements and gene expression by affecting R-loop and 5hmC crosstalk. Cell reports. 2024;43:113662.
Kang K, Bachu M, Park SH, Kang K, Bae S, Park-Min KH, et al. IFN-gamma selectively suppresses a subset of TLR4-activated genes and enhancers to potentiate macrophage activation. Nat Commun. 2019;10:3320.
Wang J, Conlon D, Rivellese F, Nerviani A, Lewis MJ, Housley W, et al. Synovial inflammatory pathways characterize anti-TNF-responsive rheumatoid arthritis patients. Arthritis Rheumatol. 2022;74:1916–1927.
Rivellese F, Surace AEA, Goldmann K, Sciacca E, Cubuk C, Giorli G, et al. Rituximab versus tocilizumab in rheumatoid arthritis: synovial biopsy-based biomarker analysis of the phase 4 R4RA randomized trial. Nat Med. 2022;28:1256–1268.
Humby F, Durez P, Buch MH, Lewis MJ, Rizvi H, Rivellese F, et al. Rituximab versus tocilizumab in anti-TNF inadequate responder patients with rheumatoid arthritis (R4RA): 16-week outcomes of a stratified, biopsy-driven, multicentre, open-label, phase 4 randomised controlled trial. Lancet. 2021;397:305–317.
Van Raemdonck K, Umar S, Palasiewicz K, Meyer A, Volin MV, Chang HJ, et al. Metabolic reprogramming of macrophages instigates CCL21-induced arthritis. Immunol Cell Biol. 2022;100:127–135.
Umar S, Palasiewicz K, Van Raemdonck K, Volin MV, Romay B, Amin MA et al. IRAK4 inhibition: a promising strategy for treating RA joint inflammation and bone erosion. Cell Mol Immunol. 2021;18:2199–2210.
Zack SR, Venkatesan M, Nikolaienko R, Cook B, Melki R, Zima AV, et al. Altered vacuole membrane protein 1 (VMP1) expression is associated with increased NLRP3 inflammasome activation and mitochondrial dysfunction. Inflamm Res. 2024;73:563–580.
Shahrara S, Proudfoot AE, Woods JM, Ruth JH, Amin MA, Park CC, et al. Amelioration of rat adjuvant-induced arthritis by Met-RANTES. Arthritis Rheum. 2005;52:1907–1919.
Xia Y, Sun J. Applied microbiome statistics: correlation, association, interaction and composition. Biometrics; 2024.
Guo Y, Walsh AM, Fearon U, Smith MD, Wechalekar MD, Yin X, et al. CD40L-dependent pathway is active at various stages of rheumatoid arthritis disease progression. J Immunol. 2017;198:4490–4501.
Umar S, Palasiewicz K, Volin MV, Zanotti B, Al-Awqati M, Sweiss N, et al. IRAK4 inhibitor mitigates joint inflammation by rebalancing metabolism malfunction in RA macrophages and fibroblasts. Life Sci. 2021;287:120114.